Piperdine derivatives in an antitussive composition and method

ABSTRACT

Piperidine derivatives with a cyano group in four-position and acid addition salts thereof possessing useful antitussive action; therapeutic compositions containing these piperidine derivatives or their pharmaceutically acceptable acid addition salts for producing antitussive effects in warm-blooded animals, particularly mammals. An illustrative embodiment is 1-(2phenylethyl)isonipecotonitrile.

United States Patent Kuhnis et a].

[ 51 July25, 1972 [54] PIPERDINE DERIVATIVES IN AN ANTITUSSIVECOMPOSITION AND METHOD [7 2] Inventors: Hans Herbert Kuhnis; Denss Rolf,both of Basel, Switzerland [52] U.S. Cl ..424/267 [51] Int. Cl. ...A61k27/00 [58] Field of Search [56] References Cited UNITED STATES PATENTS3,338,9l0 8/1967 Kiihnis et al. .260/294.3

Primary ExaminerStanley J. Friedman Attorney-Karl F. Jorda and Bruce M.Collins [57] ABSTRACT Piperidine derivatives with a cyano group infour-position and acid addition salts thereof possessing usefulantitussive action; therapeutic compositions containing these piperidinederivatives or their pharmaceutically acceptable acid addition salts forproducing antitussive effects in warm-blooded animals, particularlymammals. An illustrative embodiment is 1-(2-phenylethyl)isonipecotonitrile.

2 Claims, No Drawings PIPERDINE DERIVATIVES IN AN ANTITUSSIVECOMPOSITION AND METHOD CROSS-REFERENCE TO RELATED APPLICATION This is adivisional application of Ser. No. 739,194, filed June 24, 1968, nowU.S. Pat. No. 3,551,431.

The invention relates to piperidine derivatives of the general Formula Iwherein R is phenyl(lower)alkyl with at most nine carbon atoms,

and

R is allyl or propinyl and their addition salts with inorganic andorganic acids, have valuable pharmacological properties, in particularantitussive activity with, at the same time, a favorable therapeuticindex.

The antitussive activity of the compounds of general Formula l forinstance the hydrochlorides of 1-( 2-phenylethyl)-4- allylisonipecotonitrile, l-(2-phenylethyl)-4-(2-propinyl)-isonipecetonitrile, l-( 3-phenylpropyl)-4-allyl isonipecotonitrile andl-(3-phenylpropyl)-4-(2-propinyl)- isonipecotonitrile, can bedemonstrated, e.g., on intravenous administration in the cat by themethod according to R. Domenjoz, Arch. exp. Path. und Pharmakol. 215,19-24 1952).

Another method for proving the antitussive activity is the determinationofthe tussive irritation in the guinea pig, caused by sulphur dioxide,by subcutaneous or oral administration of the test substances. In apreliminary test to select test animals, male guinea pigs in a perspexchamber were exposed at atmospheric pressure to an SO /CO air mixture ata constant ratio of 20 ml: 1 .5 liters: 10.5 liters per minute until theonset of cough or for a maximum of 120 seconds. The onset of cough wasassessed visually. The guinea pigs reacting with cough (about two-thirdsof all animals) were put in groups of six animals each. About 24 hoursafter the preliminary test, these groups of test animals received thetest substance administered in different doses suitable for ascertainingthe E.D. in mg./kg. subcutaneously or by mouth. Exposure to irritant gaswas effected in the same way as in the preliminary test either 30 or 90minutes after administration of the test substances. The onset of coughwas again assessed visually.

The dosage preventing onset of cough in 50 percent of the animals ED isobtained by interpolation on the probability graph Schleicher & Schull298 /2 from the percentages of animals no longer reacting to SO withdifferent dosages of test substances.

The new piperidine derivatives of general Formula I and theirpharmaceutically acceptable acid addition salts are suitable as activesubstances for pharmaceutical preparations for the treatment of coughs,particularly for the amelioration and relief of tussive irritation. Theycan be administered orally, rectally or parenterally to warm-bloodedanimals, particularly mammals To produce the new piperidine derivativesof the general Formula 1 and their acid addition salts, an amide of thegeneral Formula II R: CONH2 I H2 CH2 wherein R and R have the meaningsgiven in Formula I, is reacted with an agent splitting off water and, ifdesired, the compound obtained of the general Formula I is convertedinto an addition salt with an inorganic or organic acid. Thionylchloride, phosphorus trichloride and phosphorus pentoxide are mentionedas examples of agents which split off water. The water is split off,e.g., by boiling an amide of the general Formula II with thionylchloride in benzene or chloroform or by heating with phosphoruspentoxide, preferably at temperatures between and 200, or by heatingwith phosphorus trichloride.

Starting materials of the general Formula II are obtained, e.g., byreacting the isonipecotamide with reactive esters of compounds of thegeneral Formula II],

R,OH (Ill) and further by condensation with allyl or (2-propinyl)halides with potassium amide in liquid ammonia.

According to a second process, compounds of the general Formula I andtheir addition salts with inorganic and organic acids, are produced byreacting an alkali metal compound of an isonipecotonitrile of thegeneral formula IV R1 (IV) wherein Y represents an alkali metal ion,particularly lithium ion and R has the meaning given in Formula I, in aninert organic solvent with a reactive ester of allyl alcohol or2-propinl-ol and, if desired, converting the compound obtained ofgeneral Formula I into an addition salt with an inorganic or organicacid.

As reactive esters of the allyl alcohol or 2-propin-l-ol, par ticularlythe halides such as the bromide, iodide and chloride, also alkane andarene sulphonic acid esters such as methane or p-toluene sulphonic acidesters, are used.

A mixture of abs. diethyl ether or tetrahydrofuran with 1,2-dimethoxyethane (ethylene glycol dimethyl ether) is suitable as reactionmedium for the main reaction. The alkali metal compounds of generalFormula IV are produced in situ from other suitable alkali metalcompounds. Triphenylmethyl lithium which is particularly suitable assuch, is also preferably formed in situ from another organic lithiumcompound such as phenyl lithium, for example, by adding a solution oftriphenylmethane in 1,2-dimethoxyethane to the phenyl lithium producedin the known way, which is present in diethyl ether. As thetriphenylmethyl lithium produces intensively colored solutions, itsformation as well as its use can be easily followed by theisonipecotonitrile which is subsequently added. Also ma s...

which is already embraced by general Formula I and in which R, has themeaning given in Formula I, with hydrogen until the equimolar amount hasbeen taken up, in the presence of a catalyst suitable for the partialhydrogenation of triple bonds. As catalyst, e.g., palladium on CaCO-partially deactivated with lead acetate, in ethanol as solvent andfurther deactivated in situ by the addition of quinoline, (Lindlarcatalyst, ef. Helv. Chim. Acta 35,450 (1952), is used. If desired, thecompound obtained of general Formula I is converted into an additionsalt with an inorganic or organic acid.

If desired, the piperidine derivatives of the general Formula I obtainedby the processes according to the invention are then converted intotheir addition salts with inorganic and organic acids in the usual way.For example, the acid desired as salt component or a solution thereof isadded to a solution of a piperidine derivative of the general Formula Iin an organic solvent such as diethyl ether, methanol or ethanol, andthe salt which precipitates either direct or after addition of a secondorganic liquid, e.g., diethyl ether to methanol, is isolated.

For use as active substances in therapeutic compositions,pharmaceutically acceptable acid addition salts can be used instead offree bases, i.e., salts with those acids the anions of which have nopharmacological action or which in themselves have a desiredpharmacological action. In addition, it is of advantage if the salts tobe used as active substances crystallize well and are not or are onlyslightly hygroscopic. Hydrochloric acid, hydrobromic acid, sulphuricacid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid,fl-hydroxyethane sulphonic acid, acetic acid, malic acid, tartaric acid,citric acid, lactic acid, succinic acid, fumaric acid, maleic acid,benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, embonicacid, or 1,5-naphthalene disulphonic acid, for example, can be used forsalt formation with piperidine derivatives of the general Formula l.

The new piperidine derivatives of the general Formula l and their saltsmay be administered orally, rectally or parenteraily. The daily dosagesof free bases or of pharmaceutically acceptable salts thereof varybetween about 0.02 mg/kg and about mg/kg, preferably about 0.05 mg/kg toabout 5.0 mg/kg for mammals, depending on the mammal and condition.Suitable dosage units such as dragees (sugar-coated tablets), capsules,tablets, suppositories or ampoules, preferably contain l-l00 mg ofpiperidine derivative of the general formula I or of a pharmaceuticallyacceptable salt thereof.

Dosage units for oral administration preferably contain between 1percent and 90 percent of a piperidine derivative of general Formula Ior of a pharmaceutically acceptable salt thereof as active substance.They are produced by combining the active substance with, e.g., solid,pulverulent carriers such as lactose sucrose, sorbitol, mannitol;starches such as potato v starch, maize starch or amylopectin, alsolaminaria powder or citrus pulp powder; cellulose derivatives orgelatine, optionally with the addition of lubricants such as magnesiumor calcium stearate or polyethylene glycols, to form tablets of drageecores. The latter are coated, e.g., with concentrated sugar solutionswhich can also contain, e.g., gum arabic, talcum and/or titaniumdioxide, or with a lacquer dissolved in easily volatile organic solventsor mixtures of solvents. Dyestuffs can be added to these coatings, e.g.,to distinguish between varying dosages of active substance. Othersuitable dosage units for oral administration are hard gelatine capsulesand also soft, closed capsules made of gelatine and a softener such asglycerin. The former preferably contain the active substance as agranulate in admixture with lubricants such as talcum or magnesiumstearate and, optionally, stabilizers such as sodium metabisulphite orascorbic acid. In soft capsules, the active substance is preferablydissolved or suspended in suitable liquids such as liquid polyethyleneglycols to which stabilizers can also be added.

Also, for the treatment of coughs, e.g., lozenges as well as forms notmade up into single dosages can be used for oral administration, e.g.,cough syrups or drops prepared with the usual auxiliaries.

Dosage units for rectal administration are, e.g., suppositories whichconsist of a combination of a piperidine derivative of the generalformula I or a suitable salt thereof with a neutral fatty foundation, oralso gelatine rectal capsules which contain a combination of the activesubstance with polyethylene glycols.

Ampoules for parenteral, particularly intramuscular, also intravenous,administration preferably contain a water-soluble salt of a piperidinederivative of the general formula I as active substance in aconcentration of, preferably, 0.5-5 percent, in aqueous solution,optionally together with suitable stabilizers and buffer substances.

The following prescriptions further illustrate the production of formsfor administration according to the invention:

a. 10 g of active substance, 3.g. l-(2-phenylethyl)-4-allylisonipecotonitrile hydrochloride, 30 g. of lactose and 5 g. of highlydispersed silicic acid are mixed, the mixture is moistened with asolution of 5 g. of gelatine and 7.5 g. of glycerin in distilled waterand granulated through a sieve. The granuiate is dried, sieved andcarefully mixed with 3.5 g. of potato starch, 3.5 g. of talcum and 0.5g. of magnesium stearate. The mixture is compressed into 1,000 tabletseach weighing 65 mg. and containing 10 mg. of active substance.

b. Five g. of active substance, e.g. l-(2-phenylethyl)-4-( 2-propinyl)-isonipecotonitrile hydrochloride, l5 g. of lactose and 20 g.of starch are mixed. The mixture is moistened with a solution of 5 g ofgelatine and 7.5 g of glycerin in distilled water and granulated througha sieve. The granulate is dried, sieved and carefully mixed with 3.5 gof talcum and 0.5 g of magnesium stearate. The mixture is compressedinto 1,000 dragee cores. These are then coated with a concentrated syrupmade from 26.66 g of crystallized sucrose, g g of talcum, l g. ofshellac, 3.75 g. of gum arabic, l g of highly dispersed silicic acid and0.090 g of dyestuff, and dried. The dragees obtained each weigh l 10 mg.and contain 5 mg of active substance.

c. 1,000 capsules each containing l0 mg. of active substance areproduced as fOllows: 10 g of l-(2-phenylethyl)-4- allylisonipecotonitrile hydrochloride are mixed with 263 g of lactose. Themixture is evenly moistened with an aqueous solution of 2 g. of gelatineand granulated through a suitable sieve (e.g., sieve Ill, Ph. Helv. V).The granulate is mixed with l0 g. of dried maize starch and 15 g. oftalcum and is then evenly filled into 1,000 hard gelatine capsules, sizel.

d. A cough syrup containing 0.5 percent active substance is prepared asfollows: 1.5 liters of glycerin, 42 g. of p-hydroxybenzoic acid methylester, 18 g. of p-hydroxybenzoic acid npropyl ester and, while slightlywarming, 50 g. of l-(2-phenylethyl)-4-allyl isonipecotonitrilehydrochloride are dissolved in 3 liters of distilled water. Four litersof 70 percent sorbitol solution, l,000 g. of crystallized sucrose, 350 9of glucose and a flavoring, e.g., 250 g. of Orange Peel Soluble Fluidproduced by Eli Lilly & Co. Indianapolis or 5 g. of natural lemonfavoring and 5 g. of Halb and l-lalb" essence, both produced undHaarmann und Reimer, Holzminden, Germany, are added. The solutionobtained is filtered and the filtrate is made up to 10 liters withdistilled water.

e. A cough syrup containing 0.25 percent of active substance is producedas follows: 25 g. of l-(2-phenylethyl)-4- allyl isonipecotonitrilehydrochloride is dissolved by warming in a mixture of 2.5 liters ofwater, and 0.5 liters of 96 percent ethanol. Also, a syrup is made from30 liters of water, 1 liter of 70 percent sorbitol solution, 3,000 g. ofcrystallized sucrose, 42 g. of p-hydroxybenzoic acid methyl ester and 18g. of phydroxy-benzoic acid n-propyl ester, and this syrup is carefullymixed with the solution of active substance. After the addition offlavorings, e.g. those mentioned under ((1) and, if necessary,filtration, the syrup obtained is made up to 10 liters with distilledwater.

f. For the treatment of coughs, drops containing 2.5 percent of activesubstance are prepared by dissolving 250 g. of i-( 2-phenylethyl)-4-allyl isonipectonitrile hydrochloride and 30 g. of sodiumcyclamate in a mixture of 4 liters of 96 percent ethanol and 1 liter ofpropylene glycol. Also, 3.5 liters of 70 percent sorbitol solution aremixed with 1 liter of water and this mixture is added to the abovesolution of active substance. A flavoring, e.g., 5 g. of coughdrop aromaor 30 g. of grapefruit essence, both produced by Haarmann and Reimer,Holzminden, Germany, is added and the whole is well mixed, filtered andmade up to liters with distilled water.

g. A mass for suppositories is made from 2.5 g. of 1-(2-phenylethyl)-4-allyl isonipecotonitrile hydrochloride and 167.5 g. ofAdeps solidus and 100 suppositories are filled therewith. Each contains25 mg. of active substance.

h. Two g. of 1-(2-phenylethyl)-4-allyl isonipecotonitrile hydrochlorideand 2.2 g. of glycerin are dissolved in distilled water up to 100 ml.and the solution is filled into 100 ampoules. Each contains 1 ml. and 20mg. of active substance.

The following examples illustrate the production of the new compounds ofgeneral Formula I but in no way limit the scope of the invention. Thetemperatures are given in degrees centigrade.

EXAMPLE 1 Thirty ml of thionyl chloride are carefully added to asolution of 25.4 g l-(2-phenylethyl)-4-allyl isonipecotinic acid amidein 75 ml of chloroform. An exothermic reaction takes place. The reactionmixture is then refluxed for 5 hours. The chloroform and thionylchloride are then evaporated off in vacuo, the residue is decomposedwith water while cooling, made alkaline with concentrated ammonia and isextracted several times with ether. The combined ether extracts aredried and concentrated. The residue is distilled. The l-(2-phenylethyl)-4-allyl isonipecotonitrile boils at l26l39/0.2 torr. Thehydrochloride prepared with hydrogen chloride melts at 293294 whenrecrystallized from methanol.

EXAMPLE 2 4.5 g of bromobenzene in 60 ml. of abs. ether are placed in a200 ml four-necked flask and, while stirring under an atmosphere ofnitrogen, 0.40 g of lithium wire cut into small pieces are addedwhereupon the ether begins to boil. After the reaction has subsided themixture is refluxed for another 2% hours. 6.35 g. of triphenylmethane in25 ml. of abs. l,2-dimethoxyethane are added all at once to the solutionof phenyl lithium obtained whereupon, due to the formation oftriphenylmethyl lithium, the solution turns deep red and gently boils.After stirring for 20 minutes at room temperature, 5.5 g. of l-(Z-phenylethyl)-isonipecotonitrile in 5 ml. of abs. ether are added at29. The solution loses its deep red color and the temperature slightlyrises. It is stirred for 10 minutes at room temperature and then 3.4 g.of allyl bromide in 20 ml. of abs. ether are added all at once. Themixture is stirred for 2% hours at room temperature whereupon it turnsyellowish and lithium bromide precipitates. 20 ml. of water are thenadded to the reaction mixture which is then evaporated in a rotaryevaporator. Ether is added to the residue and the ether solutionobtained is extracted four times with dilute hydrochloric acid. The acidextracts are made alkaline and exhaustively extracted with chloroform.The chloroform extracts are dried and concentrated. The residue is takenup in ether, the ether solution is dried and concentrated and theresidue is distilled. The l-(2-phenylethyl)-4-allyl isonipecotonitrileboils at l26l 39/0.2 torr. The hydrochloride prepared with hydrogenchloride in ether melts, after recrystallization from methanol, at M.P.293294.

On using the corresponding l-substituted isonipecotonitrile, thefollowing compound is obtained analogously: l-( 3-phenylpropyl)-4-allylisonipecotonitrile, hydrochloride 2 l 9-220.

The starting material is produced as follows:

a. 35.0 g of isonipecotinic acid amide, 2-phenylethyl bromide 46.0 g ofsodium carbonate and 0.3 g of sodium iodide and 200 ml of diethyl ketoneare refluxed for 4 hours. The reaction mixture is then filtered undersuction and the residue is washed several times with hot acetone. Thewhole filtrate is evaporated in vacuo and the crystalline residue isrecrystallized from ethanol/methanol. The l-( 2-phenyl-ethyl)-isonipecotinic acid amide so obtained melts at l78-179.

b. 19.8 g. of l-(2-phenylethyl)-isonipecotinic acid amide are dissolvedin 75 ml of chloroform and, in all, 50 ml. of thionyl chloride arecarefully added to the solution, whereupon the temperature of thesolution rises. It is then refluxed for 5 hours, after which chloroformand thionyl chloride are evaporated in vacuo, the residue is decomposedwith an alkaline reaction with concentrated ammoniawhile cooling withwater and it is extracted several times with ether. The combined etherextracts are dried and concentrated and the residue is distilled. Thel-(2-phenylethyl)-isonipecotonitrile passes over at l24-l29 under 001torr. The hydrochloride prepared with ethereal hydrogen chloridesolution melts at 2l6-2l8.

The folling is produced in an analogous way:l-(3-phenylpropyl)-isonipecotonitrile, B.P. l38-l39/0.07 torr,hydrochloride M.P. l77-l 78.

EXAMPLE 3 5.5 g of bromobenzene in 50 ml of abs. ether are placed in a200 ml four-necked flask and, while stirring under an atmosphere ofnitrogen, 0.49 g of lithium wire which has been cut into small piecesand washed with petroleum ether, are added whereupon the ether begins toboil. After the reaction has subsided, the mixture is refluxed foranother 2% hours. 7.6 g. of triphenylmethane in 25 ml of abs.1,2-dimethoxyethane are added all at once to the solution of phenyllithium obtained, whereupon, due to the formation of triphenylmethyllithium, the solution becomes deep red colored and gently boils. Afterstirring for 20 minutes at room temperature, 6.4 g. of 1-(Z-phenylethyl)-isonipecotonitrile (cf. example 1) in 5 ml of abs. etherare added at 28. The temperature slightly rises and the solution losesits deep red color. It is stirred for 10 minutes at room temperature andthen 4.0 g of propargyl bromide (3-bromopropine) in 20 ml. of abs. etherare added all at once. The mixture is stirred for 2% hours at roomtemperature whereupon it turns yellowish and lithium bromideprecipitates. Twenty ml of water are then added to the reaction mixtureand it is evaporated in a rotary evaporator. Ether is added to theresidue and the ether solution obtained is extracted four times withdilute hydrochloric acid. The acid extracts are made alkaline andexhaustively extracted with chloroform. The chloroform extracts aredried and evaporated. The residue is taken up in ether, the ethersolution is dried and concentrated and the residue is distilled. The l-(2-phenylethyl-4-( 2-propinyl)-isonipecotonitrile passes over atl4l170/0.05 torr.

The hydrochloride is produced therefrom in ether and recrystallized fromisopropanol/methanol. The1-(2-phenylethyl)-4-(2-propinyl)-isonipecotonitrile hydrochlorideobtained melts at 258-259.

On using the corresponding l-substituted isonipecotonitrile, thefollowing compound is obtained analogously: l-( 3-phenylpropyl )-4-(2-propinyl)-isonipecotonitrile, B.P. -1 70 /0.04 torr (airbath),hydrochloride 208-2 l 0.

EXAMPLE 4 A solution of 2.52 g. of l-(2-phenylethyl)-4-(2-propinyl)-isonipecotonitrile in 50 ml. of ethanol is hydrogenated at roomtemperature under normal pressure in the presence of 0.5 g. of Lindlarcatalyst (palladium on calcium carbonate, partially deactivated withlead acetate) and 0.2 g. of quinoline. After about 107 percent of thetheoretically necessary amount of hydrogen has been taken up, thehydrogenation is discontinued, the catalyst is filtered off andthoroughly washed with ethanol. The filtrate is evaporated in a rotaryevaporator and the residue is distilled under high vacuum. Thel-(2-phenylethyl)-4-allyl isonipecotonitrile obtained boils at l26-l39/0.2 torr. The hydrochloride prepared with hydrogen chloride wherejrL isrecrystallized from methanol whereupon it melts at 29329 R isphenyl(lower)alkyl with at most 9 carbon atoms; and

What IS claimed is: v R2 is n or propinyl l. A therapeutical compositionfor producing antitussive efor a pharmaceutical), acceptable acidaddition salt th f i fects comprising a pharmaceutical carrier and anantitussively dsage unit form aceeptable for internal administrationeffective amount of a compound of the formula C N R1\C/ 1 O 2. A methodfor treating a mammal suffering from tussive irritation comprisingadministering to said mammal an antitus- C sively effective amount of acompound as defined in claim 1. H C Hz I 11, 7 1s it i i

2. A method for treating a mammal suffering from tussive irritationcomprising administering to said mammal an antitussively effectiveamount of a compound as defined in claim